- Tenney, Alan P;
- Di Gioia, Silvio Alessandro;
- Webb, Bryn D;
- Chan, Wai-Man;
- de Boer, Elke;
- Garnai, Sarah J;
- Barry, Brenda J;
- Ray, Tammy;
- Kosicki, Michael;
- Robson, Caroline D;
- Zhang, Zhongyang;
- Collins, Thomas E;
- Gelber, Alon;
- Pratt, Brandon M;
- Fujiwara, Yuko;
- Varshney, Arushi;
- Lek, Monkol;
- Warburton, Peter E;
- Van Ryzin, Carol;
- Lehky, Tanya J;
- Zalewski, Christopher;
- King, Kelly A;
- Brewer, Carmen C;
- Thurm, Audrey;
- Snow, Joseph;
- Facio, Flavia M;
- Narisu, Narisu;
- Bonnycastle, Lori L;
- Swift, Amy;
- Chines, Peter S;
- Bell, Jessica L;
- Mohan, Suresh;
- Whitman, Mary C;
- Staffieri, Sandra E;
- Elder, James E;
- Demer, Joseph L;
- Torres, Alcy;
- Rachid, Elza;
- Al-Haddad, Christiane;
- Boustany, Rose-Mary;
- Mackey, David A;
- Brady, Angela F;
- Fenollar-Cortés, María;
- Fradin, Melanie;
- Kleefstra, Tjitske;
- Padberg, George W;
- Raskin, Salmo;
- Sato, Mario Teruo;
- Orkin, Stuart H;
- Parker, Stephen CJ;
- Hadlock, Tessa A;
- Vissers, Lisenka ELM;
- van Bokhoven, Hans;
- Jabs, Ethylin Wang;
- Collins, Francis S;
- Pennacchio, Len A;
- Manoli, Irini;
- Engle, Elizabeth C
Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.